Apolipoprotein E: Difference between revisions

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{{Infobox_gene}}
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'''Apolipoprotein E''' ('''ApoE''') is a class of proteins involved in the metabolism of fats in the body. It is important in [[Alzheimer's disease]] and [[cardiovascular disease]].<ref name="encyclopedia">{{cite book | editor-first = Ian P. | editor-last = Stolerman | name-list-format = vanc | title = Encyclopedia of Psychopharmacology | date = 2010 | publisher = Springer | location = Berlin | isbn = 978-3540686989 | edition = Online }}</ref>
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Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein ([[apolipoprotein]]) that is part of the [[chylomicron]] and [[intermediate density lipoprotein|intermediate-density lipoprotein (IDLs)]]. These are essential for the normal processing ([[catabolism]]) of [[triglyceride]]-rich lipoproteins.<ref name="entrez">{{cite web | title = Entrez Gene: APOE apolipoprotein E| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = }}</ref> In peripheral tissues, ApoE is primarily produced by the [[liver]] and [[macrophages]], and mediates [[cholesterol]] metabolism. In the [[central nervous system]], ApoE is mainly produced by [[astrocytes]] and transports [[cholesterol]] to [[neurons]] via ApoE receptors, which are members of the [[low density lipoprotein receptor gene family]].<ref>{{cite journal | vauthors = Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G | title = Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy | journal = Nature Reviews. Neurology | volume = 9 | issue = 2 | pages = 106–18 | date = February 2013 | pmid = 23296339 | doi = 10.1038/nrneurol.2012.263 | pmc=3726719}}</ref> ApoE is the principal [[cholesterol]] carrier in the brain.<ref>{{cite journal | vauthors = Puglielli L, Tanzi RE, Kovacs DM | title = Alzheimer's disease: the cholesterol connection | language = en | journal = Nature Neuroscience | volume = 6 | issue = 4 | pages = 345–51 | date = April 2003 | pmid = 12658281 | doi = 10.1038/nn0403-345 }}</ref>
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==Structure==
 
===Gene===
 
The gene, ''APOE'', is mapped to [[chromosome 19 (human)|chromosome 19]] in a cluster with [[apolipoprotein C1]] (APOC-I) and the [[apolipoprotein C2]]. The APOE gene consists of four [[exons]] and three [[introns]], totaling 3597 [[base pair]]s. ''APOE'' is transcriptionally activated by the [[liver X receptor]] (an important regulator of [[cholesterol]], [[fatty acid]], and [[glucose]] [[homeostasis]]) and [[peroxisome proliferator-activated receptor]] γ, [[nuclear receptor]]s that form [[heterodimer]]s with [[retinoid X receptor]]s.<ref name="pmid11172721">{{cite journal | vauthors = Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P | title = A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis | journal = Molecular Cell | volume = 7 | issue = 1 | pages = 161–71 | date = January 2001 | pmid = 11172721 | doi = 10.1016/S1097-2765(01)00164-2 }}</ref> In [[Melanocyte|melanocytic cells]] APOE gene expression may be regulated by [[Microphthalmia-associated transcription factor|MITF]].<ref name="pmid19067971">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–76 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x }}</ref>
 
===Protein===
APOE is 299 [[amino acid]]s long and contains multiple [[amphipathic]] [[α-helices]]. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed [[hydrophobic]] surface and interact with those in the N-terminal helix bundle domain through [[hydrogen bond]]s and salt-bridges. The C-terminal region also contains a [[low density lipoprotein receptor]] (LDLR)-binding site.<ref name="pmid25328986">{{cite journal | vauthors = Phillips MC | title = Apolipoprotein E isoforms and lipoprotein metabolism | journal = IUBMB Life | volume = 66 | issue = 9 | pages = 616–23 | date = September 2014 | pmid = 25328986 | doi = 10.1002/iub.1314 }}</ref>
 
===Polymorphisms===
{{Infobox single nucleotide polymorphism
| rsid        = 429358
| name_1      =
| name_2      =
| name_3      =
| gene        = ApoE
| chromosome  = 19
| region      =
| alfred      =
| alzgene_geneid =
| alzgene_polyid =  
| pdgene_geneid =  
| pdgene_polyid =
| szgene_geneid =
| szgene_polyid =
}}
}}
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''APOE'' is [[Polymorphism (biology)|polymorphic]],<ref name="pmid17092867">{{cite journal | vauthors = Singh PP, Singh M, Mastana SS | title = APOE distribution in world populations with new data from India and the UK | journal = Annals of Human Biology | volume = 33 | issue = 3 | pages = 279–308 | year = 2006 | pmid = 17092867 | doi = 10.1080/03014460600594513 }}</ref><ref name="10.1002/ajpa.21298">{{cite journal | vauthors = Eisenberg DT, Kuzawa CW, Hayes MG | title = Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history | journal = American Journal of Physical Anthropology | volume = 143 | issue = 1 | pages = 100–11 | date = September 2010 | pmid = 20734437 | doi = 10.1002/ajpa.21298 }}</ref> with three major [[allele]]s (epsilon 2, epsilon 3, and epsilon 4): ''APOE-ε2'' (cys112, cys158), ''APOE-ε3'' (cys112, arg158), and ''APOE-ε4'' (arg112, arg158).<ref name="encyclopedia"/><ref name="cardiogenetics"/><ref>{{cite journal | vauthors = Ghebranious N, Ivacic L, Mallum J, Dokken C | title = Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology | journal = Nucleic Acids Research | volume = 33 | issue = 17 | pages = e149 | year = 2005 | pmid = 16204452 | pmc = 1243648 | doi = 10.1093/nar/gni155 }}</ref>
{{GNF_Protein_box
Although these allelic forms differ from each other by only one or two [[amino acid]]s at positions 112 and 158,<ref>{{OMIM|107741#0015|APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive}}</ref><ref>{{OMIM|107741#0001|APOE3 isoform, APOE, CYS112 and ARG158}}</ref><ref name="pmid16603077">{{cite journal | vauthors = Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J | authorlink2=Christopher H. van Dyck | title = Variation at APOE and STH loci and Alzheimer's disease | journal = Behavioral and Brain Functions | volume = 2 | issue = 1 | pages = 13 | year = 2006 | pmid = 16603077 | pmc = 1526745 | doi = 10.1186/1744-9081-2-13 }}</ref> these differences alter APOE structure and function. These have physiological consequences:
| image = PBB_Protein_APOE.jpg
 
  | image_source = [[Protein_Data_Bank|PDB]] rendering based on 1b68.
* ε2 (rs7412-T, rs429358-T) has an [[allele frequency]] of approximately 7 percent.<ref name="Meta-analysis">{{cite web|title=Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies |url=http://www.alzgene.org/meta.asp?geneID=83 |deadurl=yes |archiveurl=https://web.archive.org/web/20121124082912/http://www.alzgene.org/meta.asp?geneID=83 |archivedate=2012-11-24 }}</ref> This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.<ref>{{cite journal | vauthors = Weisgraber KH, Innerarity TL, Mahley RW | title = Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site | journal = The Journal of Biological Chemistry | volume = 257 | issue = 5 | pages = 2518–21 | date = March 1982 | pmid = 6277903 }}</ref> E2 is associated with both increased and decreased risk for [[atherosclerosis]]. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the [[genetic disorder]] [[type III hyperlipoproteinemia]]—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age).<ref>{{cite journal | vauthors = Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ | title = Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2 | journal = Journal of Lipid Research | volume = 23 | issue = 8 | pages = 1224–35 | date = November 1982 | pmid = 7175379 }}</ref><ref>{{cite journal | vauthors = Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W | title = Molecular basis of type III hyperlipoproteinemia in Germany | journal = Human Mutation | volume = 11 | issue = 6 | pages = 417–23 | year = 1998 | pmid = 9603433 | doi = 10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5 }}</ref><ref>{{cite journal | vauthors = Civeira F, Pocoví M, Cenarro A, Casao E, Vilella E, Joven J, González J, Garcia-Otín AL, Ordovás JM | title = Apo E variants in patients with type III hyperlipoproteinemia | journal = Atherosclerosis | volume = 127 | issue = 2 | pages = 273–82 | date = December 1996 | pmid = 9125318 | doi = 10.1016/S0021-9150(96)05969-2 }}</ref> E2 has also been implicated in [[Parkinson's disease]],<ref>{{cite journal | vauthors = Huang X, Chen PC, Poole C | title = APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease | journal = Neurology | volume = 62 | issue = 12 | pages = 2198–202 | date = June 2004 | pmid = 15210882 | doi = 10.1212/01.wnl.0000130159.28215.6a }}</ref> but this finding was not replicated in a larger population association study.<ref>{{cite journal | vauthors = Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB | title = A large study reveals no association between APOE and Parkinson's disease | journal = Neurobiology of Disease | volume = 46 | issue = 2 | pages = 389–92 | date = May 2012 | pmid = 22349451 | pmc = 3323723 | doi = 10.1016/j.nbd.2012.02.002 }}</ref>
* ε3 (rs7412-C, rs429358-T) has an allele frequency of approximately 79 percent.<ref name="Meta-analysis"/> It is considered the "neutral" Apo E genotype.
| Name = Apolipoprotein E
* {{anchor|E4}}ε4 (rs7412-C, rs429358-C) has an allele frequency of approximately 14 percent.<ref name="Meta-analysis"/> E4 has been implicated in [[atherosclerosis]],<ref name="pmid3283935">{{cite journal | vauthors = Mahley RW | title = Apolipoprotein E: cholesterol transport protein with expanding role in cell biology | journal = Science | volume = 240 | issue = 4852 | pages = 622–30 | date = April 1988 | pmid = 3283935 | doi = 10.1126/science.3283935 }}</ref> [[Alzheimer's disease]],<ref name="pmid8346443">{{cite journal | vauthors = Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA | title = Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families | journal = Science | volume = 261 | issue = 5123 | pages = 921–23 | date = August 1993 | pmid = 8346443 | doi = 10.1126/science.8346443 }}</ref><ref name="pmid8446617">{{cite journal | vauthors = Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD | title = Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 5 | pages = 1977–81 | date = March 1993 | pmid = 8446617 | pmc = 46003 | doi = 10.1073/pnas.90.5.1977 }}</ref> impaired [[cognitive function]],<ref>{{cite journal | vauthors = Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ | title = Cognitive change and the APOE epsilon 4 allele | journal = Nature | volume = 418 | issue = 6901 | pages = 932 | date = August 2002 | pmid = 12198535 | doi = 10.1038/418932a }}</ref><ref name="Cognitive Impairment">{{cite journal | vauthors = Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC | title = Impact of APOE in mild cognitive impairment | journal = Neurology | volume = 63 | issue = 10 | pages = 1898–901 | date = November 2004 | pmid = 15557508 | doi = 10.1212/01.wnl.0000144279.21502.b7 }}</ref> reduced [[hippocampal]] volume,<ref name="Cognitive Impairment"/> [[HIV]],<ref>{{cite journal | vauthors = Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK | title = Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 25 | pages = 8718–23 | date = June 2008 | pmid = 18562290 | doi = 10.1073/pnas.0803526105 | pmc=2438419}}</ref> faster disease progression in [[multiple sclerosis]],<ref>{{cite journal | vauthors = Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD | title = APOE genotype is a major predictor of long-term progression of disability in MS | journal = Neurology | volume = 56 | issue = 3 | pages = 312–16 | date = February 2001 | pmid = 11171894 | doi = 10.1212/wnl.56.3.312 }}</ref><ref>{{cite journal | vauthors = Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL | title = Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis | journal = American Journal of Human Genetics | volume = 70 | issue = 3 | pages = 708–17 | date = March 2002 | pmid = 11836653 | doi = 10.1086/339269 | pmc=384947}}</ref> unfavorable outcome after [[traumatic brain injury]],<ref>{{cite journal | vauthors = Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B, Groswasser Z | title = Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury | journal = Neurology | volume = 52 | issue = 2 | pages = 244–48 | date = January 1999 | pmid = 9932938 | doi = 10.1212/wnl.52.2.244 }}</ref> ischemic [[cerebrovascular disease]],<ref>{{cite journal | vauthors = McCarron MO, Delong D, Alberts MJ | title = APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis | journal = Neurology | volume = 53 | issue = 6 | pages = 1308–11 | date = October 1999 | pmid = 10522889 | doi = 10.1212/wnl.53.6.1308 }}</ref> [[sleep apnea]],<ref>{{cite journal | vauthors = Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM, Mignot E | title = Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults | journal = JAMA | volume = 285 | issue = 22 | pages = 2888–90 | date = June 2001 | pmid = 11401610 | doi = 10.1001/jama.285.22.2888 }}</ref><ref>{{cite journal | vauthors = Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T | title = APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study | journal = Neurology | volume = 63 | issue = 4 | pages = 664–68 | date = August 2004 | pmid = 15326239 | doi = 10.1212/01.wnl.0000134671.99649.32 }}</ref> accelerated [[telomere]] shortening <ref name="pmid23418430">{{cite journal | vauthors = Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL | title = Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use | journal = PLOS One | volume = 8 | issue = 2 | pages = e54713 | date = February 2013 | pmid = 23418430 | pmc = 3572118 | doi = 10.1371/journal.pone.0054713 }}</ref> and reduced [[neurite]] outgrowth.<ref name="pmid18395206">{{cite journal | vauthors = Raber J | title = AR, apoE, and cognitive function | journal = Hormones and Behavior | volume = 53 | issue = 5 | pages = 706–15 | date = May 2008 | pmid = 18395206 | pmc = 2409114 | doi = 10.1016/j.yhbeh.2008.02.012 }}</ref> A notable advantage of the E4 allele (relative to E2 and E3) is a positive association with higher levels of [[vitamin D]], which may help explain its prevalence despite its seeming complicity in various diseases or disorders.<ref name="pmid-21659554">{{cite journal | vauthors = Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G | title = APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans | journal = FASEB Journal | volume = 25 | issue = 9 | pages = 3262–70 | date = September 2011 | pmid = 21659554 | doi = 10.1096/fj.11-180935 }}</ref>
| HGNCid = 613
| Symbol = APOE
| AltSymbols =; AD2; MGC1571; apoprotein
| OMIM = 107741
| ECnumber =
| Homologene = 30951
| MGIid = 88057
| GeneAtlas_image1 = PBB_GE_APOE_203382_s_at_tn.png
  | GeneAtlas_image2 = PBB_GE_APOE_203381_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_APOE_212884_x_at_tn.png
| Function = {{GNF_GO|id=GO:0001540 |text = beta-amyloid binding}} {{GNF_GO|id=GO:0005319 |text = lipid transporter activity}} {{GNF_GO|id=GO:0005543 |text = phospholipid binding}} {{GNF_GO|id=GO:0008034 |text = lipoprotein binding}} {{GNF_GO|id=GO:0008201 |text = heparin binding}} {{GNF_GO|id=GO:0016209 |text = antioxidant activity}} {{GNF_GO|id=GO:0048156 |text = tau protein binding}} {{GNF_GO|id=GO:0050749 |text = apolipoprotein E receptor binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0042627 |text = chylomicron}}  
| Process = {{GNF_GO|id=GO:0000302 |text = response to reactive oxygen species}} {{GNF_GO|id=GO:0006707 |text = cholesterol catabolic process}} {{GNF_GO|id=GO:0006869 |text = lipid transport}} {{GNF_GO|id=GO:0006874 |text = cellular calcium ion homeostasis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0007010 |text = cytoskeleton organization and biogenesis}} {{GNF_GO|id=GO:0007271 |text = synaptic transmission, cholinergic}} {{GNF_GO|id=GO:0007611 |text = learning and/or memory}} {{GNF_GO|id=GO:0008015 |text = circulation}} {{GNF_GO|id=GO:0030516 |text = regulation of axon extension}} {{GNF_GO|id=GO:0042157 |text = lipoprotein metabolic process}} {{GNF_GO|id=GO:0042311 |text = vasodilation}} {{GNF_GO|id=GO:0042632 |text = cholesterol homeostasis}} {{GNF_GO|id=GO:0046907 |text = intracellular transport}} {{GNF_GO|id=GO:0048168 |text = regulation of neuronal synaptic plasticity}} {{GNF_GO|id=GO:0051262 |text = protein tetramerization}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 348
    | Hs_Ensembl = ENSG00000130203
    | Hs_RefseqProtein = NP_000032
    | Hs_RefseqmRNA = NM_000041
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 19
    | Hs_GenLoc_start = 50100879
    | Hs_GenLoc_end = 50104489
    | Hs_Uniprot = P02649
    | Mm_EntrezGene = 11816
    | Mm_Ensembl = ENSMUSG00000002985
    | Mm_RefseqmRNA = NM_009696
    | Mm_RefseqProtein = NP_033826
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 18854795
    | Mm_GenLoc_end = 18857574
    | Mm_Uniprot = Q3TX45
  }}
}}
{{SI}}


==Overview==
However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer’s Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.<ref>{{cite journal | vauthors = Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K | title = Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers | journal = Cerebral Cortex | volume = 17 | issue = 8 | pages = 1934–47 | date = August 2007 | pmid = 17077159 | doi = 10.1093/cercor/bhl103 }}</ref>
'''Apolipoprotein E''' (APOE) is an [[apoprotein]] found in the [[chylomicron]] that binds to a specific [[Receptor (biochemistry)|receptor]] on [[hepatocyte|liver cell]]s and peripheral cells.
<!-- This summary is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells.  ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.  The APOE gene is mapped to chromosome 19 in a cluster with APOC1 and APOC2. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants.<ref name="entrez">{{cite web | title = Entrez Gene: APOE apolipoprotein E| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = }}</ref>
}}


==Function==
== Function ==
APOE<ref>{{cite journal |author=Singh PP, Singh M, Mastana SS |title=Genetic variation of apolipoproteins in North Indians |journal=Hum. Biol. |volume=74 |issue=5 |pages=673-82 |year=2002 |pmid=12495081 |doi=}}</ref> is essential for the normal [[catabolism]] of [[triglyceride]]-rich [[lipoprotein]] constituents. APOE was initially recognized for its importance in lipoprotein metabolism and [[cardiovascular disease]]. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including [[Alzheimer's disease]]  (AD), immunoregulation, and cognition. Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for [[cerebral palsy]], according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in [[familial dysbetalipoproteinemia]], or type III [[hyperlipoproteinemia]] (HLP III), in which increased plasma [[cholesterol]] and triglycerides are the consequence of impaired clearance of [[chylomicron]], [[VLDL]] and [[LDL]] remnants.
APOE transports [[lipid]]s, fat-soluble [[vitamins]], and [[cholesterol]] into the [[lymph system]] and then into the blood. It is synthesized principally in the [[liver]], but has also been found in other tissues such as the [[brain]], [[kidney]]s, and [[spleen]].<ref name="cardiogenetics">{{cite book | last1 = Baars | first1 = HF | last2 = van der Smagt | first2 = JJ | last3 = Doevandans | first3 = PAFM | title = Clinical Cardiogenetics | date = 2011 | publisher = Springer | location = London | isbn = 978-1849964715 | name-list-format = vanc }}</ref> In the nervous system, non-neuronal cell types, most notably [[Astrocyte|astroglia]] and [[microglia]], are the primary producers of APOE, while neurons preferentially express the receptors for APOE.<ref>{{cite journal | vauthors = Zhang Z, Mu J, Li J, Li W, Song J | title = Aberrant apolipoprotein E expression and cognitive dysfunction in patients with poststroke depression | journal = Genetic Testing and Molecular Biomarkers | volume = 17 | issue = 1 | pages = 47–51 | date = January 2013 | pmid = 23171142 | pmc = 3525887 | doi = 10.1089/gtmb.2012.0253 }}</ref> There are seven currently identified mammalian [[Receptor (biochemistry)|receptor]]s for APOE which belong to the evolutionarily conserved LDLR family.<ref>{{cite journal | vauthors = Rogers JT, Weeber EJ | title = Reelin and apoE actions on signal transduction, synaptic function and memory formation | journal = Neuron Glia Biology | volume = 4 | issue = 3 | pages = 259–70 | date = August 2008 | pmid = 19674510 | doi = 10.1017/S1740925X09990184 }}</ref>


APOE is 299 [[amino acid]]s long and transports [[lipoprotein]]s, fat-soluble [[vitamins]], and [[cholesterol]] into the [[lymph system]] and then into the blood. It is synthesized principally in the [[liver]], but has also been found in other tissues such as the [[brain]], [[kidney]]s, and [[spleen]]. In the nervous system, non-neuronal cell types, most notably [[Astrocyte|astroglia]] and [[microglia]], are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved [[low density lipoprotein receptor gene family]].
APOE was initially recognized for its importance in lipoprotein [[metabolism]] and [[cardiovascular disease]]. Defects in APOE result in [[familial dysbetalipoproteinemia]] aka type III [[hyperlipoproteinemia]] (HLP III), in which increased plasma [[cholesterol]] and triglycerides are the consequence of impaired clearance of [[chylomicron]], [[VLDL]] and [[LDL]] remnants.<ref name="entrez"/> More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including [[Alzheimer's disease]] (AD), [[Immune system|immunoregulation]], and [[cognition]].<ref name="encyclopedia"/> Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE [[allele]], has been associated with increased calcium ion levels and apoptosis following mechanical injury.<ref>{{vcite2 journal | vauthors = Jiang L, Zhong J, Dou X, Cheng C, Huang Z, Sun X | title = Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury | journal = Neuroscience | volume = 301 | pages = 375–83 | date = Aug 2015 | pmid = 26073697 | doi = 10.1016/j.neuroscience.2015.06.005 }}</ref>


==Gene==
In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing [[T cell]] proliferation, [[macrophage]] functioning regulation, lipid antigen presentation facilitation (by [[CD1]]) <ref>{{cite journal | vauthors = van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB | title = Apolipoprotein-mediated pathways of lipid antigen presentation | journal = Nature | volume = 437 | issue = 7060 | pages = 906–10 | date = October 2005 | pmid = 16208376 | doi = 10.1038/nature04001 }}</ref> to [[Natural Killer T cell|natural killer T cell]] as well as modulation of [[inflammation]] and [[oxidation]].<ref name="pmid20182542">{{cite journal | vauthors = Zhang HL, Wu J, Zhu J | title = The role of apolipoprotein E in Guillain–Barré syndrome and experimental autoimmune neuritis | journal = Journal of Biomedicine & Biotechnology | volume = 2010 | issue = | pages = 357412 | year = 2010 | pmid = 20182542 | pmc = 2825561 | doi = 10.1155/2010/357412 }}</ref> APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.<ref name="pmid24244577">{{cite journal | vauthors = Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M | title = ApoE production in human monocytes and its regulation by inflammatory cytokines | journal = PLOS One | volume = 8 | issue = 11 | pages = e79908 | year = 2013 | pmid = 24244577 | pmc = 3828220 | doi = 10.1371/journal.pone.0079908 }}</ref>
The APOE gene, ''ApoE'', is mapped to [[chromosome 19 (human)|chromosome 19]] in a cluster with [[Apolipoprotein C1]] and [[Apolipoprotein C2]]. ''ApoE'' consists of four [[exons]] and three [[introns]], totaling 3597 [[base pair]]s.   


The gene is [[Polymorphism (biology)|polymorphic]], with three major [[allele]]s, ''ApoE2'', ''ApoE3'', ''ApoE4'', which translate into three [[isoforms]] of the protein: normal - ApoE-ε3; dysfunctional - ApoE-ε2 and ApoE-ε4.  These isoforms differ from each other only by single [[amino acid]] substitutions at positions 112 and 158, but have profound physiological consequences.
==Clinical significance==


* E2 is associated with the [[genetic disorder]] [[type III hyperlipoproteinemia]] and with both increased and decreased risk for [[atherosclerosis]].
===Alzheimer's disease===


* E4 has been implicated in [[atherosclerosis]] and [[Alzheimer's disease]], impaired [[cognitive function]], and reduced [[neurite]] outgrowth.  
The E4 variant is the largest known genetic risk factor for late-onset sporadic [[Alzheimer's disease]] (AD) in a variety of ethnic groups.<ref>{{cite journal | vauthors = Sadigh-Eteghad S, Talebi M, Farhoudi M | title = Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis | journal = Neurosciences | volume = 17 | issue = 4 | pages = 321–26 | date = October 2012 | pmid = 23022896 }}</ref> However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,<ref name=":0">{{cite journal | vauthors = Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder PP, Ferrell RE | title = Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks | journal = American Journal of Human Genetics | volume = 45 | issue = 4 | pages = 586–91 | date = October 1989 | pmid = 2491016 | pmc = 1683508 }}</ref> but AD is rare among them.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A | title = Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease | journal = Neuroepidemiology | volume = 17 | issue = 1 | pages = 14–20 | date = 1998-01-01 | pmid = 9549720 | doi=10.1159/000026149}}</ref> This may be due to their low cholesterol levels.<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, Refolo LM, Pappolla M | title = Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol | journal = Journal of Molecular Neuroscience | volume = 20 | issue = 3 | pages = 395–406 | date = 2003-01-01 | pmid = 14501024 | doi = 10.1385/JMN:20:3:395 }}</ref><ref name=":2">{{cite journal | vauthors = Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H | title = Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease | journal = Annals of Internal Medicine | volume = 137 | issue = 3 | pages = 149–55 | date = August 2002 | pmid = 12160362 | doi=10.7326/0003-4819-137-3-200208060-00006}}</ref> Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with [[amyloid]].<ref name="pmid1625800">{{cite journal | vauthors = Wisniewski T, Frangione B | title = Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid | journal = Neuroscience Letters | volume = 135 | issue = 2 | pages = 235–38 | date = February 1992 | pmid = 1625800 | doi = 10.1016/0304-3940(92)90444-C }}</ref> Alzheimer's disease is characterized by build-ups of aggregates of the [[peptide]] [[beta-amyloid]]. Apolipoprotein E enhances [[proteolytic]] break-down of this peptide, both within and between cells. The [[isoform]] ApoE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.<ref name="Neuron">{{cite journal | vauthors = Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE | title = ApoE promotes the proteolytic degradation of Abeta | journal = Neuron | volume = 58 | issue = 5 | pages = 681–93 | date = June 2008 | pmid = 18549781 | pmc = 2493297 | doi = 10.1016/j.neuron.2008.04.010 | publisher = Cell Press | laydate = 2008-06-13 | laysource = ScienceDaily | laysummary = https://www.sciencedaily.com/releases/2008/06/080611135123.htm }}</ref>


''ApoE'' is a target gene of [[liver X receptor]], a [[nuclear receptor]] member that play role in [[metabolism]] regulation of [[cholesterol]], [[fatty acid]], and [[glucose]] [[homeostasis]].
Although 40–65% of AD patients have at least one copy of the ε4 allele, ''ApoE4'' is not a determinant of the disease – at least a third of patients with AD are ''ApoE4'' negative and some ''ApoE4'' homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.<ref name="HauserRyan2013">{{cite journal | vauthors = Hauser PS, Ryan RO | title = Impact of apolipoprotein E on Alzheimer's disease | journal = Current Alzheimer Research | volume = 10 | issue = 8 | pages = 809–17 | date = October 2013 | pmid = 23919769 | pmc = 3995977 | doi = 10.2174/15672050113109990156 }}</ref> There is also evidence that the ApoE2 allele may serve a protective role in AD.<ref name="pmid7920638">{{cite journal | vauthors = Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE | title = Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease | journal = Nature Genetics | volume = 7 | issue = 2 | pages = 180–84 | date = June 1994 | pmid = 7920638 | doi = 10.1038/ng0694-180 }}</ref> Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4.  Using  genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (ApoE2,4), have an odds ratio of 2.6.  Persons with one copy each of the 2 allele and the 3 allele (ApoE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (ApoE2,2) also have an odds ratio of 0.6.<ref name="ReferenceA">{{cite journal | vauthors = Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM | title = Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium | journal = JAMA | volume = 278 | issue = 16 | pages = 1349–56 | year = 1997 | pmid = 9343467 | doi = 10.1001/jama.1997.03550160069041 }}</ref>


{| class="wikitable"
{| class="wikitable"
|-
|-
|-
|-
| colspan="5"  align="center" style="color: black; background: #ccccff" | '''Estimated human genotype frequency of ApoE'''<ref>{{cite journal |
| colspan="5"  align="center" style="color: black; background: #ccccff" | '''Estimated worldwide human allele frequencies of ApoE '''* in Caucasian population<ref name="ReferenceA"/>
journal = Exp Eye Res |
volume = 2007 May;84(5):801-11. Epub 2006 Sep 26 |
title =  Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease |
author = Hill JM, Bhattacharjee PS, Neumann DM |
pmid = 17007837 }}</ref>
|-
|-
! align="center" style="color: black; background: #ccccff" |Allele
! align="center" style="color: black; background: #ccccff" |Allele
Line 88: Line 65:
! align="center" style="color: black; background: #ccccff" |ε4
! align="center" style="color: black; background: #ccccff" |ε4
|-
|-
| align="center" style="color: black; background: #ccccff" | ε2
| align="center" style="color: black; background: #ccccff" | General Frequency
| align="center" |∼1–2%
| align="center" |8.4%
| align="center" |∼15%
| align="center" |77.9%
| align="center" |∼1–2%
| align="center" |13.7%
|-
| align="center" style="color: black; background: #ccccff" | ε3
|
| align="center" |∼55%
| align="center" |∼25%
|-
|-
| align="center" style="color: black; background: #ccccff" | ε4
| align="center" style="color: black; background: #ccccff" | AD Frequency
|  
| align="center" |3.9%
|  
| align="center" |59.4%
| align="center" |∼1–2%
| align="center" |36.7%
|}
|}
While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer’s, a 2002 study concluded, that in persons with any combination of ApoE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.<ref name=":2" /> Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person’s risk for Alzheimer’s disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.<ref name=":2" />


==Alzheimer's Disease==
Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.<ref>{{Cite journal|last=Damoiseaux|first=Jessica S.|last2=Seeley|first2=William W.|last3=Zhou|first3=Juan|last4=Shirer|first4=William R.|last5=Coppola|first5=Giovanni|last6=Karydas|first6=Anna|last7=Rosen|first7=Howard J.|last8=Miller|first8=Bruce L.|last9=Kramer|first9=Joel H.|date=2012-06-13|title=Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels|url=http://www.jneurosci.org/content/32/24/8254|journal=Journal of Neuroscience|language=en|volume=32|issue=24|pages=8254–62|doi=10.1523/JNEUROSCI.0305-12.2012|issn=0270-6474|pmid=22699906|pmc=3394933}}</ref>
APOE-ε4 has been shown to cause an increased susceptibility to [[Alzheimer's disease]] (AD).<!--


--><ref name="pmid8346443">{{cite journal |author=Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA |title=Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families |journal=Science |volume=261 |issue=5123 |pages=921-3 |year=1993 |pmid=8346443 |doi=}}</ref><!--
===Atherosclerosis===
[[Knockout mouse|Knockout mice]] that lack the apolipoprotein-E gene (ApoE<sup>−/−</sup>) develop extreme [[hypercholesterolemia]] when fed a high-fat diet.<ref name="pmid20210786">{{cite journal | vauthors = McNeill E, Channon KM, Greaves DR | title = Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications | journal = Clinical Science | volume = 118 | issue = 11 | pages = 641–55 | date = June 2010 | pmid = 20210786 | doi = 10.1042/CS20090488 }}</ref>


--> The pivotal role of ''ApoE'' in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University.  Linkage studies were followed by association analysis confirming the role of the APOE-ε4 allele.
===Malaria===


Although 40-65% of AD patients have at least one copy of the 4 allele, ''ApoE4'' is not a determinant of the disease - at least a third of patients with AD are ''ApoE4'' negative and some ''ApoE4'' homozygotes never develop the disease.
ApoE<sup>−/−</sup> knockout mice show marked attenuation of cerebral [[malaria]] and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the [[blood-brain barrier]].<ref name="pmid27647324">{{cite journal | vauthors = Kassa FA, Van Den Ham K, Rainone A, Fournier S, Boilard E, Olivier M | title = Absence of apolipoprotein E protects mice from cerebral malaria | journal = Scientific Reports | volume = 6 | issue =  | pages = 33615 | date = September 2016 | pmid = 27647324 | pmc = 5028887 | doi = 10.1038/srep33615 }}</ref> Human studies have shown that the ApoE2 polymorphism correlates with earlier infection and ApoE3/4 polymorphisms increase likelihood of severe malaria.<ref name="pmid14985370">{{cite journal | vauthors = Wozniak MA, Riley EM, Itzhaki RF | title = Apolipoprotein E polymorphisms and risk of malaria | journal = Journal of Medical Genetics | volume = 41 | issue = 3 | pages = 145–46 | date = March 2004 | pmid = 14985370 | pmc = 1735716 | doi =  10.1136/jmg.2003.014613 }}</ref>


Among ApoE4 carriers, another gene, [[GAB2]], is thought to further influence the risk of getting AD.<!--
== Interactions ==


--><ref name="pmid17553421">{{cite journal |author=Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA |title=GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers |journal= |volume=54 |issue=5 |pages=713-720 |year=2007 |pmid=17553421 |doi=10.1016/j.neuron.2007.05.022}} [http://www.neuron.org/content/article/fulltext?uid=PIIS0896627307003790&highlight=GAB2 Free full text] [http://download.neuron.org/pdfs/0896-6273/PIIS0896627307003790.pdf Free PDF] [http://www.tgen.org/research/index.cfm?pageid=1065 Genetic data in the public domain]</ref>
===Interactive pathway map===
{{StatinPathway WP430|highlight=Apolipoprotein_E}}


A confirmatory cohort study conducted by the Dutch in rotterdam, examining a total of 6,713 elderly people at risk of developing dementia found that there was an increased risk of developing Alzheimers, and with it dementia, when ApoE4 gene was present however this was not significant.<!--
==Evolution==
--><ref name="PMID17110278">http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=16857570&cmd=showdetailview&indexed=google</ref>


There is also evidence that the 2 allele may serve a protective role in AD.<!--
Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.<ref name="Babin_1997">{{cite journal | vauthors = Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B | title = Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development | journal = PNAS | volume = 94 | issue = 16 | pages = 8622–27 | year = 1997 | pmid = 9238027 | pmc = 23048 | doi = 10.1073/pnas.94.16.8622}}</ref>  Proteins similar in function have been found in choanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals.  It is believed that the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.<ref name="Huebbe_2017">{{cite journal | vauthors = Huebbe P, Rimbach G | title = Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors | journal = Ageing Research Reviews | volume = 37 | issue = | pages = 146–61 | year = 2017 | pmid = 28647612 | doi = 10.1016/j.arr.2017.06.002 }}</ref>


--><ref name="pmid7920638">{{cite journal |author=Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE |title=Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease |journal=Nat. Genet. |volume=7 |issue=2 |pages=180-4 |year=1994 |pmid=7920638 |doi=10.1038/ng0694-180}}</ref>
The three major human alleles (E4, E3, E2) arose after the primate-human split around 7.5 million years ago.  These alleles are the by-product of non-synonymous mutations which led to changes in functionality.  The first allele to emerge was E4.  After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V174L, A18T, A135V), but the fourth substitution traded a threonine for an arginine altering the protein's functionality.  This substitution occurred somewhere in the 6 million year gap between the primate-human split and the Denisovan-human split, since the exact same substitutions were found in Denisovan APOE.<ref name="McIntosh_2012">{{cite journal | vauthors = McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, Fontenot MB, Bradley BJ | title = The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes) | journal = PLOS One | volume = 7 | issue = 10 | pages = e47760 | year = 2012 | pmid = 23112842 | pmc = 3480407 | doi = 10.1371/journal.pone.0047760 }}</ref>


Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4.  The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are.  The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease.  The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease.  Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.
About 220,000 years ago, an arginine to cysteine substitution took place at amino acid 112 (Arg112Cys) of the APOE4 gene and this resulted in the E3 allele.  Finally, 80,000 years ago another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.<ref name="pmid15101252">{{cite journal | vauthors = Finch CE, Stanford CB | title = Meat-adaptive genes and the evolution of slower aging in humans | journal = The Quarterly Review of Biology | volume = 79 | issue = 1 | pages = 3–50 | year = 2004 | pmid = 15101252 | doi = 10.1086/381662 }}</ref><ref name="Huebbe_2017" />


==References==
== References ==
{{reflist|2}}
{{Reflist}}
==Further reading==


{{refbegin | 2}}
== Further reading ==
{{PBB_Further_reading
{{Refbegin|33em}}
| citations =
* {{cite journal | vauthors = Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G | title = Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy | journal = Nature Reviews. Neurology | volume = 9 | issue = 2 | pages = 106–18 | date = February 2013 | pmid = 23296339 | doi = 10.1038/nrneurol.2012.263 | pmc=3726719}}
*{{cite journal | author=Mahley RW |title=Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. |journal=Science |volume=240 |issue= 4852 |pages= 622-30 |year= 1988 |pmid= 3283935 |doi= }}
* {{cite journal | vauthors = Gunzburg MJ, Perugini MA, Howlett GJ | title = Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E | journal = The Journal of Biological Chemistry | volume = 282 | issue = 49 | pages = 35831–41 | date = December 2007 | pmid = 17916554 | doi = 10.1074/jbc.M706425200 }}
*{{cite journal | author=Strittmatter WJ, Roses AD |title=Apolipoprotein E and Alzheimer disease. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 11 |pages= 4725-7 |year= 1995 |pmid= 7761390 |doi= }}
* {{cite journal | vauthors = Kolovou GD, Anagnostopoulou KK | title = Apolipoprotein E polymorphism, age and coronary heart disease | journal = Ageing Research Reviews | volume = 6 | issue = 2 | pages = 94–108 | date = August 2007 | pmid = 17224309 | doi = 10.1016/j.arr.2006.11.001 }}
*{{cite journal | author=de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM |title=Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. |journal=Hum. Mutat. |volume=4 |issue= 3 |pages= 178-94 |year= 1995 |pmid= 7833947 |doi= 10.1002/humu.1380040303 }}
* {{cite journal | vauthors = Lambert JC, Amouyel P | title = Genetic heterogeneity of Alzheimer's disease: complexity and advances |journal =[[Psychoneuroendocrinology (journal)|Psychoneuroendocrinology]] | volume = 32 Suppl 1 | issue =  | pages = S62–70 | date = August 2007 | pmid = 17659844 | doi = 10.1016/j.psyneuen.2007.05.015 }}
*{{cite journal | author=Roses AD, Einstein G, Gilbert J, ''et al.'' |title=Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism. |journal=Ann. N. Y. Acad. Sci. |volume=777 |issue=  |pages= 146-57 |year= 1996 |pmid= 8624078 |doi= }}
* {{cite journal | vauthors = Raber J | title = Role of apolipoprotein E in anxiety | journal = Neural Plasticity | volume = 2007 | issue = | pages = 91236 | year = 2007 | pmid = 17710250 | pmc = 1940061 | doi = 10.1155/2007/91236 }}
*{{cite journal | author=Beffert U, Danik M, Krzywkowski P, ''et al.'' |title=The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease. |journal=Brain Res. Brain Res. Rev. |volume=27 |issue= 2 |pages= 119-42 |year= 1998 |pmid= 9622609 |doi= }}
* {{cite journal | vauthors = Ye J | title = Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus | journal = PLoS Pathogens | volume = 3 | issue = 8 | pages = e108 | date = August 2007 | pmid = 17784784 | pmc = 1959368 | doi = 10.1371/journal.ppat.0030108 }}
*{{cite journal | author=Mahley RW, Ji ZS |title=Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. |journal=J. Lipid Res. |volume=40 |issue= 1 |pages= 1-16 |year= 1999 |pmid= 9869645 |doi= }}
* {{cite journal | vauthors = Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J | title = Association of apolipoprotein E genotypes with lipid levels and coronary risk | journal = JAMA | volume = 298 | issue = 11 | pages = 1300–11 | date = September 2007 | pmid = 17878422 | doi = 10.1001/jama.298.11.1300 }}
*{{cite journal | author=Mahley RW, Rall SC |title=Apolipoprotein E: far more than a lipid transport protein. |journal=Annual review of genomics and human genetics |volume=1 |issue= |pages= 507-37 |year= 2002 |pmid= 11701639 |doi= 10.1146/annurev.genom.1.1.507 }}
* {{cite journal | vauthors = Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA | title = The role of viruses and of APOE in dementia | journal = Annals of the New York Academy of Sciences | volume = 1019 | issue = 1 | pages = 15–18 | date = June 2004 | pmid = 15246985 | doi = 10.1196/annals.1297.003 }}
*{{cite journal | author=Parasuraman R, Greenwood PM, Sunderland T |title=The apolipoprotein E gene, attention, and brain function. |journal=Neuropsychology |volume=16 |issue= 2 |pages= 254-74 |year= 2002 |pmid= 11949718 |doi= }}
* {{cite journal | vauthors = Ashford JW | title = APOE genotype effects on Alzheimer's disease onset and epidemiology | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 157–65 | year = 2004 | pmid = 15181244 | doi = 10.1385/JMN:23:3:157 }}
*{{cite journal | author=Bocksch L, Stephens T, Lucas A, Singh B |title=Apolipoprotein E: possible therapeutic target for atherosclerosis. |journal=Current drug targets. Cardiovascular & haematological disorders |volume=1 |issue= 2 |pages= 93-106 |year= 2003 |pmid= 12769659 |doi= }}
* {{cite journal | vauthors = Huang Y, Weisgraber KH, Mucke L, Mahley RW | title = Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 189–204 | year = 2004 | pmid = 15181247 | doi = 10.1385/JMN:23:3:189 }}
*{{cite journal | author=Masterman T, Hillert J |title=The telltale scan: APOE epsilon4 in multiple sclerosis. |journal=Lancet neurology |volume=3 |issue= 6 |pages= 331 |year= 2004 |pmid= 15157846 |doi= 10.1016/S1474-4422(04)00763-X }}
* {{cite journal | vauthors = Masterman T, Hillert J | title = The telltale scan: APOE epsilon4 in multiple sclerosis | journal = The Lancet. Neurology | volume = 3 | issue = 6 | pages = 331 | date = June 2004 | pmid = 15157846 | doi = 10.1016/S1474-4422(04)00763-X }}
*{{cite journal | author=Ashford JW |title=APOE genotype effects on Alzheimer's disease onset and epidemiology. |journal=J. Mol. Neurosci. |volume=23 |issue= 3 |pages= 157-65 |year= 2004 |pmid= 15181244 |doi= }}
* {{cite journal | vauthors = Bocksch L, Stephens T, Lucas A, Singh B | title = Apolipoprotein E: possible therapeutic target for atherosclerosis | journal = Current Drug Targets. Cardiovascular & Haematological Disorders | volume = 1 | issue = 2 | pages = 93–106 | date = December 2001 | pmid = 12769659 | doi = 10.2174/1568006013337944 }}
*{{cite journal | author=Huang Y, Weisgraber KH, Mucke L, Mahley RW |title=Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. |journal=J. Mol. Neurosci. |volume=23 |issue= 3 |pages= 189-204 |year= 2004 |pmid= 15181247 |doi= }}
* {{cite journal | vauthors = Mahley RW, Rall SC | title = Apolipoprotein E: far more than a lipid transport protein | journal = Annual Review of Genomics and Human Genetics | volume = 1 | issue = 1 | pages = 507–37 | year = 2002 | pmid = 11701639 | doi = 10.1146/annurev.genom.1.1.507 }}
*{{cite journal | author=Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA |title=The role of viruses and of APOE in dementia. |journal=Ann. N. Y. Acad. Sci. |volume=1019 |issue= |pages= 15-8 |year= 2004 |pmid= 15246985 |doi= 10.1196/annals.1297.003 }}
* {{cite journal | vauthors = Parasuraman R, Greenwood PM, Sunderland T | title = The apolipoprotein E gene, attention, and brain function | journal = Neuropsychology | volume = 16 | issue = 2 | pages = 254–74 | date = April 2002 | pmid = 11949718 | pmc = 1350934 | doi = 10.1037/0894-4105.16.2.254 }}
*{{cite journal | author=Kolovou GD, Anagnostopoulou KK |title=Apolipoprotein E polymorphism, age and coronary heart disease. |journal=Ageing Res. Rev. |volume=6 |issue= 2 |pages= 94-108 |year= 2007 |pmid= 17224309 |doi= 10.1016/j.arr.2006.11.001 }}
* {{cite journal | vauthors = Mahley RW, Ji ZS | title = Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E | journal = Journal of Lipid Research | volume = 40 | issue = 1 | pages = 1–16 | date = January 1999 | pmid = 9869645 | doi = }}
*{{cite journal | author=Lambert JC, Amouyel P |title=Genetic heterogeneity of Alzheimer's disease: complexity and advances. |journal=Psychoneuroendocrinology |volume=32 Suppl 1 |issue= |pages= S62-70 |year= 2007 |pmid= 17659844 |doi= 10.1016/j.psyneuen.2007.05.015 }}
* {{cite journal | vauthors = Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J | title = The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease | journal = Brain Research. Brain Research Reviews | volume = 27 | issue = 2 | pages = 119–42 | date = July 1998 | pmid = 9622609 | doi = 10.1016/S0165-0173(98)00008-3 }}
*{{cite journal | author=Raber J |title=Role of apolipoprotein E in anxiety. |journal=Neural Plast. |volume= |issue= |pages= 91236 |year= 2007 |pmid= 17710250 |doi= 10.1155/2007/91236 }}
* {{cite journal | vauthors = Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, Hulette C, Masliah E, Pericak-Vance MA, Saunders AM, Schmechel DE, Strittmatter WJ, Weisgraber KH, Xi PT | title = Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism | journal = Annals of the New York Academy of Sciences | volume = 777 | issue = 1 | pages = 146–57 | date = January 1996 | pmid = 8624078 | doi = 10.1111/j.1749-6632.1996.tb34413.x }}
*{{cite journal | author=Ye J |title=Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus. |journal=PLoS Pathog. |volume=3 |issue= 8 |pages= e108 |year= 2007 |pmid= 17784784 |doi= 10.1371/journal.ppat.0030108 }}
* {{cite journal | vauthors = Strittmatter WJ, Roses AD | title = Apolipoprotein E and Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4725–27 | date = May 1995 | pmid = 7761390 | pmc = 41779 | doi = 10.1073/pnas.92.11.4725 }}
*{{cite journal | author=Bennet AM, Di Angelantonio E, Ye Z, ''et al.'' |title=Association of apolipoprotein E genotypes with lipid levels and coronary risk. |journal=JAMA |volume=298 |issue= 11 |pages= 1300-11 |year= 2007 |pmid= 17878422 |doi= 10.1001/jama.298.11.1300 }}
* {{cite journal | vauthors = de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM | title = Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels | journal = Human Mutation | volume = 4 | issue = 3 | pages = 178–94 | year = 1995 | pmid = 7833947 | doi = 10.1002/humu.1380040303 }}
*{{cite journal | author=Utermann G, Pruin N, Steinmetz A |title=Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. |journal=Clin. Genet. |volume=15 |issue= 1 |pages= 63-72 |year= 1979 |pmid= 759055 |doi= }}
* {{cite journal | vauthors = Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S, Arakawa K | title = Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia | journal = Biochimica et Biophysica Acta | volume = 1128 | issue = 1 | pages = 58–64 | date = September 1992 | pmid = 1356443 | doi = 10.1016/0005-2760(92)90257-V }}
*{{cite journal | author=Moriyama K, Sasaki J, Matsunaga A, ''et al.'' |title=Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia. |journal=Biochim. Biophys. Acta |volume=1128 |issue= 1 |pages= 58-64 |year= 1992 |pmid= 1356443 |doi= }}
* {{cite journal | vauthors = Mahley RW | title = Apolipoprotein E: cholesterol transport protein with expanding role in cell biology | journal = Science | volume = 240 | issue = 4852 | pages = 622–30 | date = April 1988 | pmid = 3283935 | doi = 10.1126/science.3283935 }}
}}
* {{cite journal | vauthors = Utermann G, Pruin N, Steinmetz A | title = Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man | journal = Clinical Genetics | volume = 15 | issue = 1 | pages = 63–72 | date = January 1979 | pmid = 759055 | doi = 10.1111/j.1399-0004.1979.tb02028.x }}
{{refend}}
{{Refend}}
 
{{Portal|Mitochondria}}


==External links==
== External links ==
* {{MeshName|Apolipoproteins+E}}
* {{MeshName|Apolipoproteins+E}}
* [http://apoe4.info apoe4.info – website for APOE-epsilon-4 carriers]
* {{UCSC gene info|APOE}}


{{PDB Gallery|geneid=348}}
{{Lipoproteins}}
{{Lipoproteins}}
[[Category:Apolipoproteins]]
[[Category:Apolipoproteins]]
[[Category:Alzheimer's disease]]
[[Category:Alzheimer's disease]]
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[[ru:Аполипопротеин E]]
[[tr:Apolipoprotein E]]
[[zh:载脂蛋白 E]]
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Latest revision as of 19:01, 11 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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View/Edit Human

Apolipoprotein E (ApoE) is a class of proteins involved in the metabolism of fats in the body. It is important in Alzheimer's disease and cardiovascular disease.[1]

Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of the chylomicron and intermediate-density lipoprotein (IDLs). These are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins.[2] In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.[3] ApoE is the principal cholesterol carrier in the brain.[4]

Structure

Gene

The gene, APOE, is mapped to chromosome 19 in a cluster with apolipoprotein C1 (APOC-I) and the apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors.[5] In melanocytic cells APOE gene expression may be regulated by MITF.[6]

Protein

APOE is 299 amino acids long and contains multiple amphipathic α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.[7]

Polymorphisms

SNP: Apolipoprotein E
GeneApoE
Chromosome19
External databases
EnsemblHuman SNPView
dbSNP429358
HapMap429358
SNPedia429358

APOE is polymorphic,[8][9] with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158).[1][10][11] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[12][13][14] these differences alter APOE structure and function. These have physiological consequences:

However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer’s Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.[37]

Function

APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.[10] In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.[38] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.[39]

APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.[2] More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition.[1] Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.[40]

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) [41] to natural killer T cell as well as modulation of inflammation and oxidation.[42] APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.[43]

Clinical significance

Alzheimer's disease

The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.[44] However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,[45] but AD is rare among them.[45][46] This may be due to their low cholesterol levels.[45][46][47][48] Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid.[49] Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform ApoE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.[50]

Although 40–65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease – at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.[51] There is also evidence that the ApoE2 allele may serve a protective role in AD.[52] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (ApoE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (ApoE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (ApoE2,2) also have an odds ratio of 0.6.[53]

Estimated worldwide human allele frequencies of ApoE * in Caucasian population[53]
Allele ε2 ε3 ε4
General Frequency 8.4% 77.9% 13.7%
AD Frequency 3.9% 59.4% 36.7%

While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer’s, a 2002 study concluded, that in persons with any combination of ApoE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.[48] Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person’s risk for Alzheimer’s disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.[48]

Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.[54]

Atherosclerosis

Knockout mice that lack the apolipoprotein-E gene (ApoE−/−) develop extreme hypercholesterolemia when fed a high-fat diet.[55]

Malaria

ApoE−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood-brain barrier.[56] Human studies have shown that the ApoE2 polymorphism correlates with earlier infection and ApoE3/4 polymorphisms increase likelihood of severe malaria.[57]

Interactions

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Evolution

Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.[58] Proteins similar in function have been found in choanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals. It is believed that the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.[59]

The three major human alleles (E4, E3, E2) arose after the primate-human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V174L, A18T, A135V), but the fourth substitution traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate-human split and the Denisovan-human split, since the exact same substitutions were found in Denisovan APOE.[60]

About 220,000 years ago, an arginine to cysteine substitution took place at amino acid 112 (Arg112Cys) of the APOE4 gene and this resulted in the E3 allele. Finally, 80,000 years ago another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.[61][59]

References

  1. ↑ 1.0 1.1 1.2 Stolerman IP, ed. (2010). Encyclopedia of Psychopharmacology (Online ed.). Berlin: Springer. ISBN 978-3540686989.
  2. ↑ 2.0 2.1 "Entrez Gene: APOE apolipoprotein E".
  3. ↑ Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (February 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
  4. ↑ Puglielli L, Tanzi RE, Kovacs DM (April 2003). "Alzheimer's disease: the cholesterol connection". Nature Neuroscience. 6 (4): 345–51. doi:10.1038/nn0403-345. PMID 12658281.
  5. ↑ Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (January 2001). "A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis". Molecular Cell. 7 (1): 161–71. doi:10.1016/S1097-2765(01)00164-2. PMID 11172721.
  6. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  7. ↑ Phillips MC (September 2014). "Apolipoprotein E isoforms and lipoprotein metabolism". IUBMB Life. 66 (9): 616–23. doi:10.1002/iub.1314. PMID 25328986.
  8. ↑ Singh PP, Singh M, Mastana SS (2006). "APOE distribution in world populations with new data from India and the UK". Annals of Human Biology. 33 (3): 279–308. doi:10.1080/03014460600594513. PMID 17092867.
  9. ↑ Eisenberg DT, Kuzawa CW, Hayes MG (September 2010). "Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history". American Journal of Physical Anthropology. 143 (1): 100–11. doi:10.1002/ajpa.21298. PMID 20734437.
  10. ↑ 10.0 10.1 Baars HF, van der Smagt JJ, Doevandans P (2011). Clinical Cardiogenetics. London: Springer. ISBN 978-1849964715.
  11. ↑ Ghebranious N, Ivacic L, Mallum J, Dokken C (2005). "Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology". Nucleic Acids Research. 33 (17): e149. doi:10.1093/nar/gni155. PMC 1243648. PMID 16204452.
  12. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive -107741#0015
  13. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, APOE, CYS112 and ARG158 -107741#0001
  14. ↑ Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J (2006). "Variation at APOE and STH loci and Alzheimer's disease". Behavioral and Brain Functions. 2 (1): 13. doi:10.1186/1744-9081-2-13. PMC 1526745. PMID 16603077.
  15. ↑ 15.0 15.1 15.2 "Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies". Archived from the original on 2012-11-24.
  16. ↑ Weisgraber KH, Innerarity TL, Mahley RW (March 1982). "Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site". The Journal of Biological Chemistry. 257 (5): 2518–21. PMID 6277903.
  17. ↑ Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ (November 1982). "Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2". Journal of Lipid Research. 23 (8): 1224–35. PMID 7175379.
  18. ↑ Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W (1998). "Molecular basis of type III hyperlipoproteinemia in Germany". Human Mutation. 11 (6): 417–23. doi:10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5. PMID 9603433.
  19. ↑ Civeira F, Pocoví M, Cenarro A, Casao E, Vilella E, Joven J, González J, Garcia-Otín AL, Ordovás JM (December 1996). "Apo E variants in patients with type III hyperlipoproteinemia". Atherosclerosis. 127 (2): 273–82. doi:10.1016/S0021-9150(96)05969-2. PMID 9125318.
  20. ↑ Huang X, Chen PC, Poole C (June 2004). "APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease". Neurology. 62 (12): 2198–202. doi:10.1212/01.wnl.0000130159.28215.6a. PMID 15210882.
  21. ↑ Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB (May 2012). "A large study reveals no association between APOE and Parkinson's disease". Neurobiology of Disease. 46 (2): 389–92. doi:10.1016/j.nbd.2012.02.002. PMC 3323723. PMID 22349451.
  22. ↑ Mahley RW (April 1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology". Science. 240 (4852): 622–30. doi:10.1126/science.3283935. PMID 3283935.
  23. ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (August 1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science. 261 (5123): 921–23. doi:10.1126/science.8346443. PMID 8346443.
  24. ↑ Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (March 1993). "Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 90 (5): 1977–81. doi:10.1073/pnas.90.5.1977. PMC 46003. PMID 8446617.
  25. ↑ Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ (August 2002). "Cognitive change and the APOE epsilon 4 allele". Nature. 418 (6901): 932. doi:10.1038/418932a. PMID 12198535.
  26. ↑ 26.0 26.1 Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (November 2004). "Impact of APOE in mild cognitive impairment". Neurology. 63 (10): 1898–901. doi:10.1212/01.wnl.0000144279.21502.b7. PMID 15557508.
  27. ↑ Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK (June 2008). "Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression". Proceedings of the National Academy of Sciences of the United States of America. 105 (25): 8718–23. doi:10.1073/pnas.0803526105. PMC 2438419. PMID 18562290.
  28. ↑ Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD (February 2001). "APOE genotype is a major predictor of long-term progression of disability in MS". Neurology. 56 (3): 312–16. doi:10.1212/wnl.56.3.312. PMID 11171894.
  29. ↑ Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL (March 2002). "Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis". American Journal of Human Genetics. 70 (3): 708–17. doi:10.1086/339269. PMC 384947. PMID 11836653.
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